Abstract
Cigarette smoke (CS) exposure is the predominant risk factor for the development of chronic obstructive pulmonary disease (COPD) and the third leading cause of death worldwide. We aimed to elucidate whether mitochondrial respiratory inhibition and oxidative stress are triggers in its etiology. In different models of CS exposure, we investigated the effect on lung remodeling and cell signaling of restoring mitochondrial respiratory electron flow using alternative oxidase (AOX), which bypasses the cytochrome segment of the respiratory chain. AOX attenuated CS-induced lung tissue destruction and loss of function in mice exposed chronically to CS for 9 months. It preserved the cell viability of isolated mouse embryonic fibroblasts treated with CS condensate, limited the induction of apoptosis, and decreased the production of reactive oxygen species (ROS). In contrast, the early-phase inflammatory response induced by acute CS exposure of mouse lung, i.e., infiltration by macrophages and neutrophils and adverse signaling, was unaffected. The use of AOX allowed us to obtain novel pathomechanistic insights into CS-induced cell damage, mitochondrial ROS production, and lung remodeling. Our findings implicate mitochondrial respiratory inhibition as a key pathogenic mechanism of CS toxicity in the lung. We propose AOX as a novel tool to study CS-related lung remodeling and potentially to counteract CS-induced ROS production and cell damage.
Keywords:
COPD; alternative oxidase; cigarette smoke; mitochondria.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Cell Movement / drug effects
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Cigarette Smoking / adverse effects*
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Complex Mixtures / pharmacology
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Disease Models, Animal
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Electron Transport Chain Complex Proteins / genetics
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Electron Transport Chain Complex Proteins / metabolism
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Embryo, Mammalian
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Female
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Fibroblasts / enzymology
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Gene Expression
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Lung / drug effects
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Lung / enzymology
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Lung / physiopathology
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Macrophages / drug effects
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Macrophages / metabolism
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Macrophages / pathology
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Mice
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Mice, Transgenic
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Mitochondria / drug effects
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Mitochondria / metabolism*
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Mitochondria / pathology
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Mitochondrial Proteins / genetics*
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Mitochondrial Proteins / metabolism
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Neutrophils / drug effects
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Neutrophils / metabolism
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Neutrophils / pathology
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Nicotiana / adverse effects*
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Nicotiana / chemistry
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Oxidative Stress
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Oxidoreductases / genetics*
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Oxidoreductases / metabolism
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Plant Proteins / genetics*
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Plant Proteins / metabolism
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Primary Cell Culture
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Pulmonary Disease, Chronic Obstructive / chemically induced
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Pulmonary Disease, Chronic Obstructive / enzymology
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Pulmonary Disease, Chronic Obstructive / genetics*
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Pulmonary Disease, Chronic Obstructive / physiopathology
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Reactive Oxygen Species / agonists
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Reactive Oxygen Species / antagonists & inhibitors
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Reactive Oxygen Species / metabolism
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Signal Transduction
Substances
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Complex Mixtures
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Electron Transport Chain Complex Proteins
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Mitochondrial Proteins
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Plant Proteins
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Reactive Oxygen Species
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Oxidoreductases
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alternative oxidase